Although CD44 is a very prominent CSC antigen, only few CAR-based approaches targeting CD44 have been developed. Early approaches that entered clinical trials included monoclonal antibodies and antibody-conjugates. First studies involving 186Re-conjugated antibody against the splice variant CD44v6 showed advantageous effects at first, however a long-term stable disease was only observed in one patient (570, 571). Likewise, the CD44-directed monoclonal antibody RG7356 showed only modest success in clinical trials with AML patients (572) and solid tumors (468). Tijink et al. coupled the CD44v6-directed antibody bivatuzumab to the cytotoxic antimicrotubule agent mertansine to produce an antibody-prodrug conjugate (573). Bivatuzumab mertansine was administered to seven patients and two of them showed stable disease during the therapy phase. However, one patient with squamous cell carcinoma of the esophagus died after treatment due to toxic epidermal necrolysis, which caused the premature cancelation of this trial (573). Because of this fatality, two clinical trials that were conducted in parallel for patients with metastatic breast cancer (574) and head and neck squamous cell carcinoma (575) had to be terminated.